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SPECIAL ARTICLE

Japanese gastric cancer treatment guidelines 2014 (ver. 4)

Japanese Gastric Cancer Association1

Received: 13 May 2016 / Accepted: 2 June 2016 / Published online: 24 June 2016

� The Author(s) 2016. This article is published with open access at Springerlink.com

Preface to the English edition

This English edition was made based on the Japanese

version published as a book in 2014. Our policy in com-

piling this edition was to attempt not to include new evi-

dence that emerged since the publication of the Japanese

version so as to maintain consistency of the two editions.

However, for some particularly important issues, we pro-

vided additional comments and new references reflecting

the new evidence.

Preface

Version 4 of the Japanese Gastric Cancer Treatment

Guidelines was completed in May 2014, incorporating new

evidence that includes those delivered as a quick bulletin in

the website of the Japan Gastric Cancer Association after

publication of the previous version. It remains largely

conformed to the textbook style, but a new section con-

sisting of clinical questions and answers (Q&A) was added

to address some important clinical issues for which hard

evidence is unavailable.

To compile this version, the guideline committee nom-

inated several working groups, each assigned to make

relevant contributions to unsolved issues on the following

topics: (1) surgery and lymphadenectomy for junctional

cancer, (2) clinical pathway, (3) follow-up after curative

surgery, (4) treatment of technically resectable metastatic

cancer, (5) risk calculation for surgical intervention and (6)

treatment of cancer of the gastric remnant. Of these, ten-

tative consensuses were reached on the first three topics

that were included as new sections in the text, whereas

further discussion was deemed necessary for the last two

topics. The clinical importance of the fourth topic and lack

of hard evidence related to that topic prompted the com-

mittee to establish a Q and A section to provide tentative

best answers to important clinical questions on technically

resectable metastatic cancer.

Major points of revision in the current version are listed

below:

1. The section on types and definitions of gastric surgery

has been revised.

2. An algorithm showing the tentative standard of the

extent of lymphadenectomy that can be recommended

for junctional cancer less than 4 cm in diameter has

been presented.

3. Laparoscopic distal gastrectomy for clinical stage I

cancer was upgraded from an investigational treatment

to an option in general practice.

4. Chemotherapeutic regimens were classified into three

recommendation categories based on the level of

evidence and consensus among the committee members.

5. A revisionwasmade to the definitionof curative resection

among tumors of expanded indication for endoscopic

resection. Additional descriptions were given on the

biopsy-derived scar and component of ‘‘muc’’ in the

submucosa of the endoscopy-resected specimen.

6. Clinical questions were raised on treatment strategy for

technically resectable metastatic cancer and chemother-

apy for patients for whom evidence-based standard

English edition editors: Yasuhiro Kodera (e-mail:

[email protected]),Takeshi Sano.

& Japanese Gastric Cancer Association

[email protected]

1 Japanese Gastric Cancer Association, 465 Kajii cho,

Kawaramachihirokoji, Kamigyo ku, Kyoto 602-8566, Japan

123

Gastric Cancer (2017) 20:1–19

DOI 10.1007/s10120-016-0622-4

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treatment may not be applicable, and the tentative but

best possible answers were provided.

7. Exemplary samples of the clinical pathway for man-

agement of patients who underwent gastrectomy and

the follow-up schedule after surgery for gastric cancer

were presented.

The description of tumor status (T/N/M and stage) in

this guideline remains to be based on the third English

edition of the Japanese Classification of Gastric Car-

cinoma [1], which is identical to that in the 7th edition

of the International Union Against Cancer (UICC)/

TNM.

Treatments

Algorithm of standard treatments to be

recommended in clinical practice

The algorithm is shown in Fig. 1.

Investigational treatments

The following treatments show promise but are as yet to be

established as the standard. They should be prospectively

evaluated in appropriate clinical research settings. Patient

consent for investigational treatments should be sought and

the rationale behind them given.

The following constitute investigational treatments:

– Endoscopic submucosal dissection under the expanded

criteria [see ‘‘Tumors indicated for endoscopic resection

as an investigational treatment (expanded indication)’’].

– Laparoscopic surgery for advanced cancer and those in

need of total gastrectomy.

– Local tumor resection.

– Neoadjuvant chemotherapy.

– Adjuvant chemotherapy using agents other than S-1.

– Neoadjuvant chemoradiotherapy.

– Adjuvant chemoradiotherapy.

Surgery

Types and definitions of gastric surgery

Curative surgery

Standard gastrectomy Standard gastrectomy is the prin-

cipal surgical procedure performed with curative intent. It

involves resection of at least two-thirds of the stomach with

a D2 lymph node dissection.

Non-standard gastrectomy In non-standard gastrectomy,

the extent of gastric resection and/or lymphadenectomy is

altered according to tumor stages.

Fig. 1 Algorithm of standard

treatments

2 Y. Kodera, T. Sano

123

Modified surgery The extent of gastric resection and/or

lymphadenectomy is reduced (D1, D1?, etc.) compared to

standard surgery.

Extended surgery (1) Gastrectomy with combined resection

of adjacent involved organs. (2) Gastrectomy with exten-

ded lymphadenectomy exceeding D2.

Non-curative surgery

Palliative surgery Serious symptoms such as bleeding or

obstruction may develop in a patient with advanced/

metastatic gastric cancer. Surgery to relieve symptoms

may then be considered an option, and palliative gas-

trectomy or gastrojejunostomy is selected depending on

the resectability of the primary tumor and/or surgical

risks. Stomach-partitioning gastrojejunostomy has been

reported to result in superior function compared to simple

gastrojejunostomy [2].

Reduction surgery The role of gastrectomy is unclear in

patients with metastatic gastric cancer in the absence of

urgent symptoms such as bleeding or obstruction. Reduc-

tion surgery aims to prolong survival or to delay the onset

of symptoms by reducing tumor volume.

(Additional comments in this English edition) No evidence

in support of reduction surgery was found in an interna-

tional cooperative randomized controlled trial (REGATTA,

JCOG0705/KGCA01 [3]).

Extent of gastric resection

Surgery for gastric cancer

Surgery for gastric cancer is defined as follows in the order

of the stomach volume to be resected.

– Total gastrectomy Total resection of the stomach

including the cardia and pylorus.

– Distal gastrectomy Stomach resection including the

pylorus. The cardia is preserved. In the standard

gastrectomy, two-thirds of the stomach is resected.

– Pylorus-preserving gastrectomy (PPG) Stomach resec-

tion preserving the upper third of the stomach and the

pylorus along with a portion of the antrum.

– Proximal gastrectomy Stomach resection including the

cardia (esophagogastric junction). The pylorus is

preserved.

– Segmental gastrectomy Circumferential resection of the

stomach preserving the cardia and pylorus.

– Local resection.

– Non-resectional surgery (bypass surgery, gastrostomy,

jejunostomy).

Determination of gastric resection

Resection margin A sufficient resection margin should be

ensured when determining the resection line in gastrectomy

with curative intent. Proximal margin of at least 3 cm is

recommended for T2 or deeper tumors with an expansive

growth pattern (types 1 and 2) and 5 cm for those with an

infiltrative growth pattern (types 3 and 4). When these rules

cannot be observed, it is advisable to examine the proximal

resection margin by frozen section. For tumors invading

the esophagus, a 5-cm margin is not necessarily required,

but frozen section examination of the resection line is

desirable to ensure an R0 resection.

For T1 tumors, a gross resection margin of 2 cm should

be obtained. When the tumor border is unclear, preopera-

tive endoscopic marking by clips of the tumor border based

on biopsy results will be helpful for decision making

regarding the resection line.

Selection of gastrectomy The standard surgical procedure

for clinically node-positive (cN?) or T2-T4a tumors is either

total or distal gastrectomy. Distal gastrectomy is selected

when a satisfactory proximal resectionmargin (see above) can

be obtained. Pancreatic invasion by tumor requiring pancre-

aticosplenectomy necessitates total gastrectomy regardless of

the tumor location. Total gastrectomy with splenectomy

should be considered for tumors that are located along the

greater curvature and harbor metastasis to no. 4sb lymph

nodes, even if the primary tumor could be removed by distal

gastrectomy. For adenocarcinoma located on the proximal

side of the esophagogastric junction, esophagectomy and

proximal gastrectomy with gastric tube reconstruction should

be considered, similarly to surgery for esophageal cancer.

For cT1cN0 tumors, the following types of gastric

resection can be considered according to tumor location.

– Pylorus-preserving gastrectomy (PPG): for tumors in

the middle portion of the stomach with the distal tumor

border at least 4 cm proximal to the pylorus.

– Proximal gastrectomy: for proximal tumors where more

than half of the distal stomach can be preserved.

– Segmental gastrectomy and local resection under

sentinel navigation are still regarded as investigational

treatments.

Lymph node dissection

Extent of lymph node dissection

The extent of systematic lymphadenectomy is defined as

follows according to the type of gastrectomy conducted.

When the extent of lymphadenectomy performed does not

Japanese gastric cancer treatment guidelines 2014 (ver. 4) 3

123

fully complywith the D level criteria, the lymph node station

that has been additionally resected or left in situ could be

recorded as in the following examples: D1 (?No. 8a), D2

(-No. 10). However, when sending data to the nationwide

database, the D level needs to be strictly decided upon and

should be downgraded if resection of any of the lymph node

stations that should have been resected was omitted.

Total gastrectomy (Fig. 2)

D0: Lymphadenectomy less than D1.

D1: Nos. 1–7.

D1?: D1 ? No. 8a, 9, 11p.

D2: D1 ? No. 8a, 9, 10, 11p, 11d, 12a.

For tumors invading the esophagus, D1? includes:

No. 110*, D2 includes No. 19, 20, 110 and 111.

Distal gastrectomy (Fig. 3)


D1: No. 1, 3, 4sb, 4d, 5, 6, 7

D1?: D1 ? No. 8a, 9

D2: D1 ? No. 8a, 9, 11p, 12a.

Pylorus-preserving gastrectomy (Fig. 4)


D1: No. 1, 3, 4sb, 4d, 6, 7.

D1?: D1 ? No. 8a, 9.

Proximal gastrectomy (Fig. 5)


D1: No. 1, 2, 3a, 4sa, 4sb, 7.

D1?: D1 ? No. 8a, 9, 11p.

For tumors invading the esophagus, D1 ? includes No.

110*.

*No. 110 lymph nodes (lower thoracic para-esophageal

nodes) in gastric cancer invading the esophagus are those

attached to the lower part of the esophagus that is removed

to obtain a sufficient resection margin.

Fig. 2 The extent of lymphadenectomy after total gastrectomy. The

numbers correspond to the lymph node station as defined in the

Japanese Classification of Gastric Carcinoma (1). Complete dissec-

tion of the nodes in blue denotes D1 dissection, the nodes in orange

D1? and the nodes in red D2

Fig. 3 The extent of lymphadenectomy after distal gastrectomy. The

numbers correspond to the lymph node station as defined in the


tion of the nodes in blue denotes D1 dissection, the nodes in orange

D1? and the nodes in red D2


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Indications for lymph node dissection

In principle, a D1 or a D1? lymphadenectomy is indicated

for cT1N0 tumors and D2 for cN? or cT2-T4 tumors. Since

the pre- and intraoperative diagnoses of lymph node metas-

tases remain unreliable, a D2 lymphadenectomy should be

performed whenever nodal involvement is suspected.

D1 lymphadenectomy A D1 lymphadenectomy is indi-

cated for T1a tumors that do not meet the criteria for EMR/

ESD, and for cT1bN0 tumors that are histologically of

differentiated type and 1.5 cm or smaller in diameter.

D1? lymphadenectomy A D1? lymphadenectomy is

indicated for cT1N0 tumors other than the above.

D2 lymphadenectomy A D2 lymphadenectomy is indi-

cated for potentially curable T2-T4 tumors as well as

cT1N? tumors. The role of splenectomy for complete

resection of Nos. 10 and 11 nodes had long been an issue of

controversy, and the final results of a randomized trial

(JCOG 0110) are awaited. In the meantime, complete

clearance of No. 10 nodes by splenectomy should be

considered for potentially curable T2-T4 tumors invading

the greater curvature of the upper stomach.

(Additional comments in this English edition) The ran-

domized trial (JCOG 0110) was concluded and revealed

non-inferiority of spleen preservation in terms of overall

survival. Splenectomy should not be performed unless the

primary T2-T4 tumor either directly invades the spleen or

is located in the greater curvature of the upper stomach [4].

D2? lymphadenectomy Gastrectomy with extended

lymphadenectomy beyond D2 is classified as a non-stan-

dard gastrectomy. Its role has been discussed as follows.

– The benefit of prophylactic para-aortic lymphadenec-

tomy was denied by the randomized trial, JCOG 9501

[5].

– Although a R0 resection may be possible for tumors

with para-aortic nodal involvement without other non-

curative factors, the prognosis of this population is

poor. Nevertheless, neoadjuvant chemotherapy fol-

lowed by D2? is a promising option (refer to CQ1).

– The role of No. 14v lymphadenectomy in distal gastric

cancer is controversial. Dissection of No. 14v had been

a part of D2 gastrectomy defined by the 13th edition of

the Japanese Classification of Gastric Carcinoma, but

was excluded from the previous version (version 3) of

the Japanese Gastric Cancer Treatment Guidelines and

remains that way in the current version. However, D2

(?No. 14v) may be beneficial for patients who are

suspected to harbor metastasis to the No. 6 nodes.

– Involvement of No. 13 nodes is defined as M1 in the

current version. However, D2 (?No. 13)

Fig. 5 The extent of lymphadenectomy after proximal gastrectomy.

The numbers correspond to the lymph node station as defined in the


tion of the nodes in blue denotes D1 dissection and the nodes in

orange D1?

Fig. 4 The extent of lymphadenectomy after pylorus-preserving

gastrectomy. The numbers correspond to the lymph node station as

defined in the Japanese Classification of Gastric Carcinoma (1).

Complete dissection of the nodes in blue denotes D1 dissection and

the nodes in orange D1?


123

lymphadenectomy may be an option in a potentially

curative gastrectomy for tumors invading the duode-

num [6].

Junctional cancer

In the Japanese Classification of Gastric Carcinoma,

junctional cancer has been defined as cancer (adenocar-

cinoma or squamous cell carcinoma) with its center

located within 2 cm of the esophago-gastric junction.

There is no consensus over the type of resection and the

extent of lymphadenectomy that could be a standard of

care for this category. In 2012–2013, the Japanese Gastric

Cancer Association and Japan Esophageal Society joined

forces to conduct a nationwide surveillance of junctional

cancer of B4 cm diameter, and retrospective data of 3177

patients operated on between 2001 and 2010 were col-

lected from 273 institutions. An algorithm showing the

tentative standard in the extent of lymphadenectomy

based on the tumor location, histology and T-categories

was constructed based on this surveillance (Fig. 6). The

anatomical border between Nos. 19 and 20 and among

Nos. 110, 111 and 112 cannot be defined clearly.

Therefore, lower mediastinal nodes and hiatal nodes were

each treated as one lymph node station in the current

analysis. Dissection of No. 3b can be omitted when per-

forming proximal gastrectomy. A prospective phase II

study by the same joint force to further investigate this

issue is on-going.

Miscellaneous

Vagal nerve preservation

It is reported that preservation of the hepatic branch of the

anterior vagus and/or the celiac branch of the posterior

vagus contributes to improving postoperative quality of life

through reducing post-gastrectomy gallstone formation,

diarrhea and/or weight loss. In case of PPG, the hepatic

branch should be preserved to maintain the pyloric function.

Omentectomy

Removal of the greater omentum is usually integrated in

the standard gastrectomy for T3 (SS) or deeper tumors. For

T1/T2 tumors, the omentum more than 3 cm away from the

gastroepiploic arcade may be preserved.

Bursectomy

For tumors penetrating the serosa of the posterior gastric

wall, bursectomy (removal of the inner peritoneal surface of

the bursa omentalis) may be performed with the aim of

removingmicroscopic tumor deposits in the lesser sac. There

is no evidence that bursectomy reduces peritoneal or local

recurrence, and it should be avoided in T1/T2 tumors to

prevent injury to the pancreas and/or adjacent blood vessels.

A small-scale randomized controlled trial recently sug-

gested a survival benefit for bursectomy in T3/T4a tumors

Fig. 6 Algorithm showing the

tentative standard in the extent

of lymphadenectomy for

junctional cancer based on the

tumor location, histology and

T-categories


123

[7]. A large-scale multi-institutional randomized trial to

address this issue (JCOG 1001) was subsequently launched

and has completed accrual.

Combined resection of adjacent organ(s)

For tumors in which the primary or metastatic lesion directly

invades adjacent organs, combined resection of the involved

organ may be performed in order to obtain an R0 resection.

Approaches to the lower esophagus

For gastric cancers invading less than 3 cm of the distal

esophagus, a transhiatal abdominal approach is recom-

mended [8]. Where a greater length of esophagus is

involved, a transthoracic approach should be considered if

the surgery is potentially curative.

Laparoscopic surgery

Laparoscopic surgery can be considered an option in gen-

eral clinical practice to treat cStage I cancer that is indi-

cated for distal gastrectomy. In the 2014 version of the

guidelines by the Japan Society for Endoscopic Surgery,

distal gastrectomy by the laparoscopic approach has been

recommended for cStage I cancer (rated recommendation

B). These decisions reflect the fact that the safety of the

laparoscopic approach was proven in a prospective phase II

study (JCOG0703) that involved only certified surgeons

with sufficient experience [9] and that superiority in terms

of short-term outcome has been reported through small-

scale randomized trials and meta-analyses. However, sur-

geons will have to be aware that the learning-curve issue

exists, and the indication for this approach should be

decided discreetly in each institution based on the expertise

of the staff members that participate in this type of surgery.

Data regarding the long-term outcome are yet to be

available, and results of pivotal phase III studies conducted

in Japan (JCOG0912 [10]) and Korea (KLASS01 [11]) are

awaited. As for more advanced cancer, there is currently no

evidence to recommend a laparoscopic approach since

randomized trials to look at safety and long-term outcome

are currently ongoing (JLSSG0901, KLASS02).

Regarding total gastrectomy by this approach, no

prospective trial has been reported. Thus, laparoscopic total

gastrectomy has been rated by the guidelines of the Japan

Society for Endoscopic Surgery (2014) as recommendation

C1 (may be considered for a patient in need of total gastrec-

tomy, but no scientific evidence in support of the procedure is

currently available). Those who consider challenging the

procedure should plan to do so with sufficient caution since

postoperative complications were reported to be significantly

more frequent in the first year of its introduction.

When conducting gastrectomy by the laparoscopic

approach, informed consent should be obtained from all

patients after providing sufficient information, including

the lack of data regarding long-term consequences.

Reconstruction after gastrectomy

The following reconstruction methods are usually

employed. Each has advantages and disadvantages. Func-

tional benefits of the pouch reconstruction are yet to be

established.

Total gastrectomy

– Roux-en-Y esophagojejunostomy.

– Jejunal interposition.

– Double tract method.

Distal gastrectomy

– Billroth I gastroduodenostomy.

– Billroth II gastrojejunostomy.

– Roux-en-Y gastrojejunostomy.


Pylorus-preserving gastrectomy

– Gastro-gastrostomy.

Proximal gastrectomy

– Esophagogastrostomy.


– Double tract method.

Endoscopic resection

Methods of endoscopic resection

Endoscopic mucosal resection (EMR)

The lesion, together with the surrounding mucosa, is lifted

by submucosal injection of saline (normo- or hypertonic)

and removed using a high-frequency steel snare.

Endoscopic submucosal dissection (ESD)

The mucosa surrounding the lesion is circumferentially

incised using a high-frequency electric knife (usually


123

insulation-tipped), and the submucosal layer is dissected

from the proper muscle layer.

Handling of endoscopically resected specimens

Handling of resected specimens

The resected specimens should be handled according to the

rules described in the Japanese Classification of Gastric

Carcinoma [1].

Definition of differentiated-type and undifferentiated-type

carcinoma

The tumor biopsy specimens and endoscopically resected

tumors are histologically classified into either the differ-

entiated or undifferentiated type. The former includes

papillary adenocarcinoma (pap) and tubular adenocarci-

noma (tub1, tub2), and the latter includes poorly differen-

tiated adenocarcinoma (por1, por2) and signet-ring cell

carcinoma (sig). Endoscopic dissection should be defined

as non-curative if mucinous adenocarcinoma (muc) was

found in the submucosal layer, regardless of whether it is

considered to derive from the differentiated or undiffer-

entiated type.

Histological predominance and intratumoral ulcerative

findings (UL)

A tumor consisting of components of both differentiated-

and undifferentiated-type carcinoma is nevertheless clas-

sified into one of the two types according to the quantita-

tive predominance. In addition, when more than one

histological type is found in a tumor, all histological types

are to be recorded in the order of quantitative predomi-

nance, e.g., tub2[ tub1. Diagnosis of UL(?) is principally

made based on the histological evidence of ulcerative

findings. However, endoscopic and/or radiological evi-

dence should also be taken into consideration when making

a conclusive diagnosis. A biopsy-derived scar is usually

observed histologically as fibrosis restricted to small areas

just beneath the muscularis mucosae. However, if it cannot

be discriminated from the ulcer scar, it should be classified

as UL(?).

Indication for endoscopic resection (Fig. 7)

Principles of indication

Endoscopic resection is considered for tumors that have a

very low possibility of lymph node metastasis and are

suitable for en-bloc resection.

Fig. 7 Algorithm showing

treatment of early gastric cancer

according to the histopathologic

findings of the specimens

resected by ESD


123

Since compilation of the first version of this guideline,

two independent sets of indications for the endoscopic

resection have been provided: an absolute indication for

standard EMR/ESD and an expanded indication for ESD to

be considered as an investigational treatment. The evidence

regarding curability of the latter technique remains insuf-

ficient, and the procedure should be offered with caution.

Tumors indicated for endoscopic resection as a standard

treatment (absolute indication)

EMR or ESD is indicated as a standard treatment for the

following tumor.

– A differentiated-type adenocarcinoma without ulcera-

tive findings [UL(-)], of which the depth of invasion is

clinically diagnosed as T1a and the diameter is B2 cm.

Tumors indicated for endoscopic resection

as an investigational treatment (expanded indication)

Tumors of the following categories have very low possi-

bility of lymph node metastasis when they are not

accompanied with lymphovascular infiltration [ly(-),

v(-)] and could be indicated for endoscopic resection

[12, 13]. To avoid incomplete dissection, ESD rather than

EMR should be performed. Since evidence on long-term

survival is currently lacking, however, endoscopic treat-

ment for these lesions should be considered investigational

until trials such as JCOG0607 turn out to be positive.

Tumors clinically diagnosed as T1a and

(a) Of differentiated-type, UL(-), but[2 cm in

diameter.

(b) Of differentiated-type, UL(?), and B3 cm in

diameter.

(c) Of undifferentiated-type, UL(-), and B2 cm in

diameter.

Local recurrence after EMR/ESD

Local mucosal recurrence after EMR/ESD for tumors that

had fulfilled the absolute indication could be considered to

meet the criteria for expanded indication and may be

treated by another ESD. However, given paucity of the

evidence in terms of long-term survival, repeat ESD should

be also considered as investigational.

Curability of endoscopic resection

Meticulous pathologic examination of the resected speci-

men is mandatory. Curability needs to be assessed based on

both the results of the pathologic examination and facts

based on the accumulated data. Two factors should be

considered for curability assessment: completeness of the

primary tumor removal and nil possibility of lymph node

metastasis.

Curative resection

The resection is determined as curative when all of the

following conditions are fulfilled: en bloc resection, tumor

size B2 cm, histologically of differentiated type, pT1a,

negative horizontal margin (HM0), negative vertical mar-

gin (VM0) and no lymphovascular infiltration (ly(-),

v(-)).

Curative resection for tumors of expanded indication

The resection is considered as curative when all of the

following conditions are fulfilled:

En bloc resection, HM0, VM0, ly(-), v(-), and

(a) Tumor size[2 cm, histologically of differentiated

type, pT1a, UL(-).

(b) Tumor size B3 cm, histologically of differentiated

type, pT1a, UL(?).

(c) Tumor size B2 cm, histologically of undifferenti-

ated type, pT1a, UL(-).

(d) Tumor size B3 cm, histologically of differentiated

type, pT1b (SM1,\500 micron from the muscularis

mucosae).

As the evidence is still insufficient for differentiated

type tumors accompanied with some areas of undifferen-

tiated type histology, the following resections are regarded

as non-curative for the time being, and addition of surgical

treatments should be recommended.

– Areas of undifferentiated type carcinoma exceed 2 cm

in the above (a).

– Undifferentiated type component in the part that had

invaded the submucosa in the above (d).

A new rule in the current version is that if a component

of undifferentiated type carcinoma was found in the above

(b) but was not the predominant histological type, risk of

nodal metastasis is estimated to be low [14], and the

endoscopic resection will be regarded as curative.

Non-curative resection

Resection that does not satisfy any of the above criteria is

considered non-curative.


123

Treatments after endoscopic resection

Treatments after curative resection

Follow-up with annual or biannual endoscopy is

recommended.

Treatments after curative resection for tumors of expanded

indications

Follow-up with abdominal ultrasonography or CT scan as

well as annual or biannual endoscopy is recommended.

In case of either ‘‘Treatments after curative resection’’ or

‘‘Treatments after curative resection for tumors of expan-

ded indications,’’ it has been recommended that Heli-

cobacter pylori be examined and, if positive, be eradicated.

However, some studies showed that Helicobacter eradica-

tion after ER had no impact on the occurrence of meta-

chronous cancer. Further investigations regarding this issue

are warranted.

Treatment after non-curative resection

Surgical treatment should be performed after non-curative

resection. However, as the following cases actually carry

very low risk for harboring lymph node metastasis, non-

surgical treatments such as repeated ESD, endoscopic

coagulation using a laser or argon-plasma coagulator, or

close observation expecting a burn effect of the initial ESD

could be proposed as alternatives and delivered upon the

patient’s informed consent.

– En bloc resection of a differentiated type carcinoma

with positive horizontal margin (HM1) as the only non-

curative factor.

– Piecemeal resection of a differentiated type carcinoma

satisfying all other criteria.

When these cases come from the category (b) or (d) of

the ‘‘Curative resection for tumors of expanded indica-

tion,’’ the size of the residual mucosal lesion should be re-

assessed by endoscopy. If the sum of the lengths of the

resected and residual lesions exceeds 3 cm, surgery is

indicated. When the positive horizontal margin or the

piecemeal resection margin involves the part of submu-

cosal invasion in category (d), surgery is indicated.

Chemotherapy

Although recent advances in chemotherapy have achieved

considerable tumor regression in many cases of unre-

sectable/recurrent gastric cancer, these responses have not

ultimately led to complete cure. The median survival time

achieved in clinical trials for the disease at this stage

remains 6–13 months. The current goal of chemotherapy

therefore is to delay the manifestation of disease-related

symptoms and/or to prolong survival. Survival benefit of

chemotherapy has been proven in randomized controlled

trials comparing chemotherapy with best supportive care

in patients with unresectable gastric cancer with perfor-

mance status (PS) of 0–2. Although very rare, some

patients with advanced disease even survive more than

5 years by chemotherapy alone. Thus, chemotherapy is

the treatment to be primarily considered for unresectable/

recurrent gastric cancer among patients with sufficiently

good PS.

Principles of indication

Chemotherapy is indicated for patients with unresectable or

recurrent disease, or those after non-curative R2 resection,

whose general condition and major organ functions are

preserved: to be specific, patients of PS 0–2, with unre-

sectable T4b disease, extensive nodal disease, hepatic

metastases, peritoneal dissemination or other M1 disease.

Recommendable regimens for Japanese patients

Treatment regimens were classified into the following three

categories according to the degree that the regimen could

be recommended. The recommendation category was

determined by the committee members based on the levels

of reported evidence and, ultimately, through consensus

reached after thorough literature review and discussion

among the members.

– Recommendation category 1: treatment regimens that

are recommended in clinical practice.

Regimens included in this category will need to be

either superior or non-inferior to the standard treatment

in a phase III trial with overall survival as the primary

endpoint. In addition, consensus must be reached

within the committee members on the interpretation

of the phase III study results, availability of the drugs in

Japan and sufficient safety and efficacy data with the

Japanese participants.


could be selected in clinical practice.

Regimens in this category include the following: (1)

those that were found to be superior or non-inferior to

the standard treatment in a phase III trial but failed to

gain sufficient support from the committee members to

be included in category 1; (2) those with sufficient

efficacy and safety data obtained in a phase II trial and

consensus reached among the committee members.


123


cannot be recommended in clinical practice.

Regimens in this category either failed to show

superiority or non-inferiority in terms of overall

survival in a phase III trial or were lacking in sufficient

efficacy/safety data with the Japanese participants.

First-line treatment

HER2 testing Since a trastuzumab-containing regimen

became the standard of care for HER2-positive gastric

cancer, HER2 testing is strongly recommended in all

patients who will undergo chemotherapy for unresectable/

metastatic gastric cancer.

HER2-negative gastric cancer S-1 ? cisplatin combina-

tion is the standard of care (recommendation category 1)

based on the results of two phase III trials conducted in

Japan (SPIRITS trial [15] and JCOG 9912 trial [16]).

Capecitabine ? cisplatin combination is currently one

of standard treatments overseas and was employed as a

control group in global phase III studies, the ToGA trial

[17] and AVAGAST trial [18]. Since subset analyses of the

Japanese participants in these trials have shown safety and

efficacy, this combination can be selected in clinical

practice (recommendation category 2).

S-1 ? docetaxel combination failed to show superiority

to S-1 monotherapy in the primary survival analysis of the

START trial conducted with the Japanese and Korean

participants, but superiority in overall survival was

observed in a reanalysis after clarifying outcome of several

censored cases [19]. This regimen could be selected for a

limited population such as those who wish to be treated at

the outpatient clinic (recommendation category 2).

Irinotecan ? cisplatin and S-1 ? irinotecan combina-

tions are not recommended as the first-line regimen

because they did not show significant superiority over 5-FU

alone and S-1 alone, respectively, in the randomized trials

conducted in Japan [16, 20] (recommendation category 3).

Regarding triplet regimens, efficacy of infusional

5FU ? cisplatin ? docetaxel was proven in the V325

study [21] conducted in the western countries. Given the

excessive toxicity and lack of data for Japanese patients,

this regimen cannot be recommended for general practice

(recommendation category 3). In Japan, a triplet consisting

of S-1, cisplatin and docetaxel (DCS regimen) is currently

being evaluated in a phase III trial, JCOG1013, following

some phase II results. Thus, the DCS regimen currently

needs to be regarded as an investigational treatment.

Evidence is lacking regarding chemotherapy for specific

types of patients such as those with no oral intake, peri-

toneal carcinomatosis (patients with a moderate to high

volume of ascites or bowel obstruction) and the elderly

(refer to CQ5 and CQ6).

(Additional comments in this English edition) Following

the results of the SOX-GC trial [22] and REAL2 trial [23],

S-1 plus oxaliplatin or capecitabine plus oxaliplatin

became options for the first-line chemotherapy and is ten-

tatively rated as recommendation category 2.

HER2-positive gastric cancer IHC3? or FISH positive

patients were eligible for the ToGA trial [17]. In the sub-

group analyses of the trial, survival benefit was more distinct

when IHC3? or FISH positive/IHC2? cohorts were selec-

ted. Thus, trastuzumab-containing regimens will be rec-

ommended for patients with IHC3? or FISH positive/

IHC2? status. Following the results of the ToGA trial, a

combination of trastuzumab, cisplatin and either capecita-

bine or infusional 5FU will be recommended for clinical

practice (recommendation category 1). A phase II trial to

explore trastuzumab combined with triweekly S-1 ? cis-

platin was conducted with promising results. However, this

combination will remain in category 2 at this time because

of the small volume of efficacy and safety data.

Second-line treatment

Second-line treatment is recommended for patients with

sufficient performance status, following several random-

ized trials mentioned below. Monotherapy with any of the

three agents, docetaxel, irinotecan or paclitaxel (weekly

administration), can be recommended (recommendation

category 1).

Randomized trials conducted in Germany [24] and

Korea [25] showed a significant survival advantage of the

second-line treatment (docetaxel or irinotecan) over the

best supportive care. A Japanese phase III trial, WJOG4007

[26], failed to prove superiority in overall survival of

irinotecan over paclitaxel (weekly administration), but did

show median survival time for both groups of approxi-

mately 9 months, which is favorable when compared with

survival data from other trials exploring the second-line

chemotherapy. This could be explained by the fact that a

high proportion of participants in this trial received another

line of treatment (taxanes among patients allocated to the

irinotecan group and irinotecan among those allocated to

the paclitaxel group). Thus, this trial indicates that patients

with good performance status could benefit from the third-

line treatments.

(Additional comments in this English edition) Following the

results of the RAINBOW trial [27] and the REGARD trial

[28], paclitaxel ? ramucirumab emerged as a new standard

of care and was rated as recommendation category 1 in the

second-line setting, while ramucirumab monotherapy was


123

rated as recommendation category 2 alongside monothera-

pies with docetaxel, irinotecan or paclitaxel, which were

relegated from recommendation category 1.

Chemotherapy as a general practice

Indication

Indication for chemotherapy should be decided after taking

into consideration the following eligibility criteria.

1. Clinical and pathological diagnosis of gastric cancer

has been obtained.

2. PS of 0–2. Generally speaking, chemotherapy is not

indicated for patients with PS of 3 or 4. Indication for

chemotherapy should be discreetly decided considering

the toxicity and benefit. The safety issue may be of

particular concern when a patient suffers from massive

ascites or overt peritoneal carcinomatosis.

3. Major organ functions are preserved.

4. Patient does not suffer from severe comorbidities.

5. Informed consent has been obtained from the patient.

Methodology

1. Prior to treatment, PS, body weight, clinical symptoms

and laboratory data (including examination for hepatitis

virus) should be checked, and imaging studies such as

computerized tomography (CT) should be performed to

obtain baseline measurements of the lesions.

2. Response to the treatment should be evaluated by

examinations that may include CT, endoscopy and

contrast radiography, followed by comparison with the

baseline data. Tumor shrinkage should be evaluated by

response criteria of the Japanese Classification of

Gastric Carcinoma or Response Evaluation Criteria in

Solid Tumors (RECIST) to decide on whether or not to

continue with the treatment.

3. When continuation of the treatment is deemed onco-

logically feasible, the drug dosage and administration

schedule should be reconsidered taking into account

the adverse events observed in the previous cycle of

treatment. Attention should also be paid to cumulative

adverse events such as skin manifestations, taste

disturbance and neurotoxicity.

4. Chemotherapy for individuals exposed or infected to

hepatitis B virus should be screened, monitored and

treated by referring to ‘‘Chapter 6.3., HBV reactiva-

tion’’ of the Japan Society of Hepatology Guidelines

for the Management of Hepatitis B Virus Infection to

prevent reactivation.

Drugs to be used

The following drugs are used in chemotherapy for gastric

cancer: fluorouracil (5FU), tegafur-gimestat-otastat potas-

sium (S-1), capecitabine, cisplatin, irinotecan, docetaxel,

paclitaxel and trastuzumab. These drugs are to be used

alone or in combination, adhering to the dose and schedule

employed when being evaluated in clinical trials.

(Additional comments in this English edition) Ramu-

cirumab and oxaliplatin can now be added to the list of the

drugs.

Postoperative adjuvant chemotherapy

Postoperative adjuvant chemotherapy is delivered with an

intention to reduce recurrence by controlling residual tumor

cells following curative resection. Various regimens had

been tested in numerous clinical trials in Japan without

producing solid evidence in support of adjuvant chemother-

apy until the efficacy of S-1 was proven in the ACTS-GC

trial [29, 30], a study that secured the place of postoperative

chemotherapy with S-1 as a standard of care (recommenda-

tion category 1). After this, the feasibility of several combi-

nations of anticancer drug with S-1 was explored in the

postoperative setting [31, 32], and some of the combinations

are currently under evaluation in phase III trials. On the other

hand, other phase III evidence in support of postoperative

chemotherapy was established in 2012 by the CLASSIC trial

conducted mainly in Korea [33], in which significant pro-

longation of recurrence-free survival was shown with a

combination of capecitabine and oxaliplatin. However,

oxaliplatin has not been approved for gastric cancer in Japan

as of 2014. Survival benefit of postoperative adjuvant

chemotherapy by combination of S-1 and another cytotoxic

drug, including oxaliplatin, will have to be proven by a

randomized trial with S-1 monotherapy as a control.

(Additional comments in this English edition) Following

the results of J-CLASSIC [34] and SOX-adjuvant trials

[35], capecitabine or S-1 plus oxaliplatin has been

approved as an adjuvant regimen in Japan.

Indications

The patients eligible for the ACTS-GC trial were those

with a tumor of pathological stage II, IIIA or IIIB,

excluding those classified as stage II due to pT1/pN2�pN3status, as defined by the previous 13th edition of the

Japanese Classification of Gastric Carcinoma (2nd English

edition), who had undergone R0 gastrectomy with CD2

lymphadenectomy. The eligibility for postoperative adju-

vant chemotherapy will remain the same in the current

version of the treatment guidelines.


123

However, in the 14th edition of the Japanese Classifi-

cation of Gastric Carcinoma (3rd English edition) whose

staging scheme is the same as the 7th edition of UICC/

TNM, stage IIA includes pT3(SS)/N0 status, which had

been rated as stage IB in the 13th edition and therefore was

ineligible for the ACTS-GC. In other words, the eligibility

criteria will remain unchanged by excluding this population

as well as the pT1/pN2�pN3 population from stage II/III.

Additionally, what has been written in ‘‘Chemotherapy as

a general practice’’ applies also to chemotherapy in the

adjuvant setting except that response to the treatment cannot

be evaluated by imaging modalities until disease recurrence.

Administration schedule

S-1 is to be started within 6 weeks from surgery, after

sufficient recovery from the surgical intervention. A

6-week cycle consisting of 4 weeks of daily oral admin-

istration of S-1 at a dose of 80 mg/m2 followed by 2 weeks

of rest is repeated during the 12 months after surgery (8

cycles). Since postoperative patients are generally more

vulnerable to both hematological and non-hematological

adverse events, appropriate dose reduction and schedule

modification should be considered, including a switch to a

schedule of 2 weeks of administration followed by 1 week

of rest.

Palliative care

Palliative care is an approach that improves the quality of

life of patients and their families facing the problems

associated with life-threatening illness through the preven-

tion and relief of suffering by means of early identification

and impeccable assessment and treatment of pain and other

problems, physical, psychosocial and spiritual (WHO Def-

inition of Palliative Care, 2002). The importance of pallia-

tive care increases incrementally as cancer progresses. The

knowledge and technique to cope with pain, to communicate

and to manage symptoms are required. Methods to accom-

plish these aims include radiotherapy and psychotherapy in

addition to medication. Various clinical studies are on-going

with particular emphasis on pain control.

Clinical pathway after surgery for gastric cancer

It is extremely difficult to establish a clinical pathway for

patients undergoing gastric cancer surgery that is widely

applicable to various surgical procedures and institutions.

However, it is possible to propose some core items based

on which individual pathways could be constructed, and

these could contribute to reducing disparities in surgical

management for gastric cancer. A basic pathway has been

constructed around the timing of some core items such as

removal of the nasogastric tube, initiation of oral fluid

intake, initiation of solid food intake, administration of

antibiotics, stoppage of intravenous fluid administration

and discharge from the hospital (Table 1). This clinical

pathway is applicable to all surgical procedures including

distal, total and proximal gastrectomy regardless of whe-

ther the surgery was performed laparoscopically or by open

approach. However, postoperative management should be

individualized for high-risk patients with severe comor-

bidities that include impaired cardiac, pulmonary, hepatic

or renal functions. Recently, investigators have been

inclined to aim for further shortening of postoperative

hospital stays through the concept of ERAS (enhanced

recovery after surgery), but the value of such programs in

gastric cancer surgery is yet to be defined.

Follow-up surveillance after surgery for gastriccancer

Follow-up at the outpatient clinic could be helpful so that

the patients can readjust to their lives at home, cope with

postgastrectomy symptoms and overcome the nutritional

Table 1 A common clinical

pathway for distal, total and

proximal gastrectomy

Clinical items Date on the clinical pathway

Removal of nasogastric tube Before or on postoperative day 1

Initiation of oral fluid intake On or after postoperative day 1

Initiation of solid food intake Between postoperative days 2–4

Prophylactic administration of antibiotics Only on the day of operation

Removal of epidural tube Before or on postoperative day 3

Removal of urinary catheter Before or on postoperative day 3

Intravenous fluid administration Until postoperative day 5–7

Removal of intra-abdominal drains Before or on postoperative day 5

Discharge from the hospital Between postoperative days 8–14


123

issues. In addition, surveillance for early detection of

recurrence and secondary cancer is usually conducted

according to the level of risk for recurrence, estimated

based on the clinical stages. However, evidence that such

surveillance actually improves survival is lacking. Due to

the paucity of prospective studies that explored follow-up

programs after gastrectomy, it is not possible to make

any recommendation on how often the examinations

should be performed, or even on which examination to

perform. However, some retrospective studies suggest

that CT, measurement of tumor markers (CEA and

CA19-9) and endoscopy are effective to detect recur-

rence, gastric remnant cancer and metachronous multiple

cancer. Tumor markers, when applicable, are apt to rise

2–3 months before metastatic lesions become

detectable by imaging modalities. Models of follow-up

programs for early-stage cancer and advanced cancer are

shown in Tables 2 and 3.

Follow-up should continue for no longer than 5 years

after which patients should be referred to regional general

physicians or should be encouraged to undergo surveillance

examinations provided as a part of health care programs in

their districts or at their places of work. In that aspect,

collaboration among various levels of medical facilities is

needed to provide comprehensive care to gastric cancer

survivors. Ultimately, there remains a need to scientifically

verify the prognostic relevance of postoperative follow-up

programs.

Appendix: clinical questions

CQ1. Should surgery be avoided in patients with gastric

cancer when metastasis to the para-aortic lymph nodes has

been detected?

Answer A multidisciplinary approach including surgery

with para-aortic lymph node dissection could be proposed

when para-aortic lymph node metastases are confined to

the No. 16 a2–b1 region, provided other non-curative

factors are absent.

Para-aortic metastases from gastric cancer are classified

as M1, and surgery with curative intent is not indicated

according to the treatment algorithm of the current guide-

lines (refer to ‘‘Algorithm of standard treatments to be

recommended in clinical practice’’).

Systemic para-aortic lymph node dissection (PAND)

had been attempted in Japan as clinical studies until its

survival benefit was denied in a randomized trial in which

only patients without lymphadenopathy in the para-aortic

region were eligible [5]. However, numerous retrospective

data from patients who underwent PAND are available in

Japan and these almost invariably indicate that (1)

metastases to the para-aortic nodes are pathologically

confirmed in a certain percentage of these patients and (2)

cure was achieved in approximately 10–20 % of the

patients who harbored metastases to the para-aortic nodes.

A similar result was recently reported from a Western

country [36]. Thus, it is not possible to totally deny the

Table 2 Postoperative follow-

up for stage I gastric cancer

patients

Duration after surgery Year: 1 1.5 2 2.5 3 4 5

Month: 1 6 12

Medical examination, PS, body weight s s s s s s s s s

Blood test including tumor markers s s s s s s s s s

CT and/or US s s s s s s

Endoscopy s s s

Examinations to be considered when needs arise: chest X-ray gastrography, barium enema, colonoscopy,

bone scintigram, PET scan

Other surveillance programs should be sought beyond the 5th year

Table 3 Postoperative follow-up for stage II–III gastric cancer patients

Duration after surgery Year: 1 2 2.5 3 3.5 4 4.5 5

Month: 1 3 6 9 12 15 18 21 24

Medical examination, PS, body weight s s s s s s s s s s s s s s s

Blood test including tumor markers s s s s s s s s s s s s s s s

CT and/or US s s s s s s s s

Endoscopy s s s

Examinations to be considered when needs arise: chest X-ray, gastrography, barium enema, colonoscopy bone scintigram, PET scan

Other surveillance programs should be sought beyond the 5th year


123

survival benefit of PAND when lymphadenopathy

restricted to the No. 16 a2–b1 region is found by preop-

erative imaging studies.

As a multidisciplinary treatment for this population, a

treatment strategy of two courses of neoadjuvant

chemotherapy with S-1 ? cisplatin followed by PAND was

explored in a phase II trial. Patients with bulky nodal disease

with or without lymphadenopathy restricted to the No. 16 a2–

b1 region were eligible, and peritoneal metastasis as well as

the CY1 status had to be ruled out by staging laparoscopy

prior to registration. Since a 5-year survival rate of 53 % was

reported in this trial [37], this treatment strategy could be

recommended for institutions with sufficient expertise in

PAND. On the other hand, there are arguments that a 5-year

survival rate of around 10 % can be achieved by

chemotherapy when the para-aortic lymph node metastasis is

the only factor that renders patients incurable [38, 39].

However, these retrospective studies are known to include

patients who eventually underwent surgery after responding

to the chemotherapy and may at least partially reflect the

benefit of the multidisciplinary approach.

CQ2. How should gastric cancer with hepatic metastases be

treated?

Answer A multidisciplinary approach including surgery

with curative intent could be proposed when the number of

metastatic nodules is small, provided other non-curative

factors are absent.

Hepatic metastases from gastric cancer are classified as

M1, and surgery with curative intent is not indicated

according to the treatment algorithm of the current guide-

lines (refer to ‘‘Algorithm of standard treatments to be

recommended in clinical practice’’).

Hepatic metastases from gastric cancer are often deemed

unresectable since they are liable to be found as multiple

nodules distributed to both hepatic lobes and are likely to be

accompanied with metastatic lesions outside of the liver. No

prospective trial exploring a benefit of hepatectomy has been

conducted, and only retrospective analyses of small cohorts

collected over several decades mostly as single-institution

studies [40–42] are available. However, 5-year survival rates

ranging from 10 to 40 % have been reported from these

studies, and one cannot deny a possibility that hepatectomy

results in long-term survival among highly selected patients.

Solitary metastasis or a small number of metastatic nodules

has been highlighted as a favorable prognostic factor in most

of the studies [43]. Given the recent advances in imaging

studies, and the fact the diagnosis of solitary metastasis

could be unreliable in older cases, hepatectomy may be

considered for patients with a small number of metastatic

nodules, and not restricted to a solitary tumor, provided that

there is no other non-curative factor. Since there was no

agreement on whether the synchronous metastases fare

better than metachronous metastases, surgery could also be

considered for recurrences in the liver if they fulfill the

conditions mentioned above. Most patients eventually suffer

from recurrences, however, and perioperative chemotherapy

could be recommended for the population that had not been

treated by adjuvant chemotherapy prior to detection of the

hepatic metastases. Evidence on which chemotherapeutic

regimen can be recommended in this particular setting,

however, is totally lacking.

CQ3. How should gastric cancer with positive peritoneal

cytology (CY1) be treated? Could there be any therapeutic

proposal for patients who underwent gastrectomy and were

found afterwards to have been CY1 (in some institutions,

results of the cytologic examination are available only after

surgery in case the sample was collected at surgery)?

Answer Multidisciplinary treatment including standard

gastrectomy can be proposed for patients with no other

non-curative factors. If the CY1 status was revealed after

surgery, postoperative treatment with S-1 can be recom-

mended as the tentative standard.

In Japan, peritoneal washing samples are usually col-

lected during surgery for cytologic examination to detect

free cancer cells. Free cancer cells in the peritoneal cavity

(CY1) are classified as M1, and surgery with curative intent

is not indicated according to the treatment algorithm of the

current guidelines (refer to ‘‘Algorithm of standard treat-

ments to be recommended in clinical practice’’). However,

patients with CY1 status are often treated by standard

gastrectomy in the absence of other no-curative factors. The

outcome of these patients had originally been dismal with a

median survival time of approximately 12 months and

5-year survival rate of 7.8 %, but such data often included

patients who were treated with surgery alone [44].

More recently, a prospective phase II study was con-

ducted in which technically resectable cancer with CY1 as

the only non-curative factor (patients with minimal and

resectable peritoneal deposits included) was treated by

standard gastrectomy followed by S-1 monotherapy until

disease progression. The median recurrence-free and

overall survival time in this study were 376 and 705 days,

and 5-year recurrence-free and overall survival rates were

21 and 26 %, respectively [45]. In addition, a single-in-

stitution retrospective study of 120 CY1 patients who

underwent surgery followed by S-1 monotherapy revealed

a 5-year survival rate of 26.6 % [46], which was compat-

ible with the trial result. These results are far better than the

results obtained before S-1 became available and are

equivalent to that of a series of curatively resected linitis

plastica-type cancers, which often recur as peritoneal dis-

ease [47]. Furthermore, CY1 patients are deemed eligible

for JCOG0501, a phase III trial to explore neoadjuvant

chemotherapy by S-1 ? cisplatin for scirrhous type gastric

cancer in which the standard treatment arm consists of

standard gastrectomy followed by S-1.


123

These facts indicate that CY1 patients could be indi-

cated for the strategy consisting of standard gastrectomy

and perioperative chemotherapy. In addition, S-1

monotherapy could be recommended for patients whose

CY1 status was informed after gastrectomy. On the other

hand, if the information on CY status was available prior to

surgery, a chemotherapy-first strategy could be taken

whereby only patients whose cytology status turned nega-

tive could be indicated for surgery [48, 49]. However,

details of the optimal multidisciplinary treatment strategy

in this setting, including the chemotherapeutic regimen to

be used and the number of cycles to be delivered, remain to

be elucidated in future clinical trials.

CQ4. Which chemotherapeutic regimen is recommended

when recurrence was detected during or within 6 months

from completion of the postoperative adjuvant

chemotherapy with S-1?

Answer Although no evidence to recommend any particular

regimen exists, most physicians would avoid monotherapy

with S-1 for second-line chemotherapy.

Postoperative adjuvant chemotherapy with S-1 has been

established as a standard of care for p-Stage II/III gastric

cancer by the ACTS-GC trial. However, the treatment for

patients who had recurrent disease after the adjuvant

treatment remains to be elucidated.

The response rate of treatment by S-1 ? cisplatin is

reportedly low (5 %) for patients who had recurrence

within 6 months from completion of the S-1 adjuvant

therapy when compared with the response rate for recur-

rences after 6 months from the completion (37.5 %) [50].

This result, found in a multi-institutional retrospective

analysis, suggests that cancers that recur during or early

after completion of an adjuvant chemotherapy are resistant

to the drug used in that chemotherapy. On the other hand, a

retrospective analysis of the patients registered for the

ACTS-GC study revealed that patients who received S-1

among other drugs in salvage line treatments survived

longer after recurrence than those who did not receive S-1,

regardless of the time interval between the adjuvant

chemotherapy and recurrence. However, results of this

study will have to be interpreted with caution since the

study suffers from several biases in the background of the

patients such as whether oral food intake was possible

(patients who did not receive S-1 after recurrence might

have been those with bowel obstruction who were unable

to eat and suffered from poor performance status).

In treatment for colorectal cancer during the era of

adjuvant chemotherapy with 5FU alone, drugs used in the

salvage line treatment depended on the time interval

between the completion of the adjuvant chemotherapy and

recurrence. New regimens have been developed as first-line

therapy for patients who had recurrence more than

6 months after completion of the adjuvant treatment and as

second line for those who had recurrence during or within

6 months of the adjuvant therapy.

The same rule has been applied for gastric cancer, and

patients with late recurrence after adjuvant treatment have

been deemed eligible for clinical trials exploring a first-line

treatment, whereas those with early recurrences were reg-

istered in clinical trials for the second-line treatment.

Thus, patients with recurrences during or early after

completion of the adjuvant treatment are considered as

targets of second-line treatments, and S-1 monotherapy is

usually avoided for this population. However, there is

currently no evidence to recommend any specific regimen

for this setting.

CQ5. Which chemotherapeutic regimen is recommended

for patients suffering from either bowel obstruction or

massive ascites due to severe peritoneal metastases?

Answer The indication for chemotherapy itself should be

decided discreetly, taking into consideration the general

status of the patient. Drugs with mild toxicity profiles such

as infusional 5-fluorouracil and paclitaxel could be con-

sidered as the candidates.

Standard of care has not been established for this pop-

ulation since the patients have not been eligible for most

clinical trials for advanced/metastatic gastric cancer. Most

patients in this population suffer from poor general status

and will not tolerate the S-1 ? cisplatin combination.

Benefit for delivering chemotherapy should be weighed

carefully against the risk, and best supportive care should

be considered as an alternative.

The JCOG0106 study was one of the few in which only

patients with peritoneal metastases detected by imaging

studies such as CT and barium enema were eligible. In this

trial, sequential therapy combining methotrexate ? 5FU,

which had been considered promising in this setting, was

explored with continuous intravenous administration of

5FU (5FUci) as a control, but failed to show a survival

benefit, while infusional 5FU was found to be less toxic

[51]. Moreover, 5FUci enabled oral food intake in 41 % (7/

27) of patients who had been unable to eat at the time of

entry to the trial. Thus, 5FUci will be the current first

choice for patients with bowel obstruction due to peritoneal

metastases, but its effect on massive ascites remains elu-

sive. On the other hand, another domestic phase III trial

(ISO-5FU10) has shown non-inferiority of the

5FU ? leucovorin (LV) combination against S-1 [52].

Thus, 5FU ? LV, which can be delivered in the outpatient

clinic, is another option for patients with relatively good

general status.

In a phase II trial exploring weekly administration of

paclitaxel in gastric cancer patients with ascites, improve-

ment in the volume of ascites evaluated by a five-point

measurement using the CT image was seen in 39 % (25/64)

of the patients [53]. In a randomized phase II trial


123

comparing second-line treatment by weekly administration

of paclitaxel with the best available 5FU (either 5FUci or

MTX ? 5FU, which was not used in the first-line treat-

ment) in patients with peritoneal metastases, a benefit in

progression-free survival was proven, but no difference

was detected in overall survival. However, paclitaxel was

associated with a more favorable toxicity profile [54].

These results indicate that weekly paclitaxel can be con-

sidered for patients with severe peritoneal disease in both

the first- and second-line setting. In addition, a phase II trial

of the FLTAX regimen, which is a combination of pacli-

taxel with 5FU ? LV, has shown that this combination

reduced ascites in 44 % of patients [55]. Further evidence

through a randomized comparison of the combination with

a single-agent treatment is awaited.

CQ6 Which chemotherapeutic regimen is recommended

for elderly patients with unresectable/advanced gastric

cancer?

Answer S-1 ? cisplatin could be recommended for fit

patients, but utmost care should be taken since the elderly

patients are generally vulnerable to the adverse events. S-1

monotherapy could be selected for more frail patients.

Although S-1 ? cisplatin is the standard first-line treat-

ment for unresectable/recurrent gastric cancer in Japan, only

patients up to 74 years of age were eligible for the SPIRITS

trial that generated this evidence, and only 17 % (50/298) of

patients registered for this trial were actually 70 years of age

or older. In a subset analysis stratified by age, the hazard ratio

of treatment by S-1 ? cisplatin versus S-1monotherapywas

0.75 (95 % CI 0.61–0.92) for patients under 60 years of age

(n = 111) as opposed to 0.98 (95 % CI 0.82–1.17) for those

between 60 and 69 and 0.95 (95 % CI 0.71–1.27) for those

between 70 and 74 [15]. Thus, a benefit of adding cisplatin is

unclear for the elderly population. In fact, there was no dif-

ference in survival between patients treated by S-1 ? cis-

platin and those treated by S-1 monotherapy in a

retrospective study of the elderly population of C70 years of

age, despite the apparent bias that the seemingly more fit

patients were selected to receive the combination therapy

[56]. Furthermore, a rather favorable outcome through S-1

monotherapy was reported in a cohort of patients C75 years

of age in a prospective phase II trial focusing on elderly

patients [57].

In short, regarding chemotherapy for advanced/meta-

static gastric cancer, the evidence generated by the general

population is unlikely to be directly applicable to elderly

patients. That said, it may still be inadequate to estimate

the tolerability of elderly patients to chemotherapy based

only on chronological age without taking into account the

major organ functions, comorbidities and past history.

Unfortunately, however, a method to comprehensively

evaluate the vulnerability of each aged individual has not

been established.

Further evidence through clinical trials is needed for

various decision-makings when treating elderly patients

with gastric cancer. Until then, whether or not to deliver

S-1 ? cisplatin to these patients will have to be decided on

a patient-by-patient basis based on the experience of each

physician. Such decision will have to be based on the

general condition of the patient with particular attention to

the renal and cardiac function, always bearing in mind that

S-1 monotherapy is quite reasonable as an alternative. Even

after the treatment has started, the patient will have to be

monitored with upmost care with attention paid not only to

severe adverse events but also to anorexia, stomatitis and

diarrhea, which could be particularly debilitating for

elderly patients.

CQ7. Which chemotherapeutic regimen is recommended as

a second-line treatment for HER2-positive gastric cancer?

Answer The taxanes or irinotecan can be recommended as

in the case of HER2-negative cancer. However, in case a

trastuzumab-containing regimen was not given as a first-

line treatment, a combination of weekly paclitaxel and

trastuzumab could be selected.

A trastuzumab-containing regimen is recommended for

the first-line treatment of HER2-positive gastric cancer as a

result of the ToGA trial [17]. There is no evidence to

recommend any specific regimen for the specific cohort of

HER2-positive patients who progressed during or after the

trastuzumab-containing regimen. Either the taxanes or

irinotecan could be selected as in the case of second-line

treatment for HER2-negative gastric cancer.

On the other hand, a promising response rate of 37.0 %

(95 % CI 23.2–52.5) and disease control rate of 82.6 %

(95 % CI 68.2–92.2) were reported in a phase II trial

exploring paclitaxel (weekly administration) ? trastuzu-

mab (JFMC45-1102 trial) for 46 evaluable patients with

HER2-positive gastric cancer who were pretreated with a

regimen that did not contain trastuzumab [58]. However,

results of this trial will have to be interpreted with care for

the following reasons: (1) Patients registered for this trial

were not a typical cohort that receives second-line

chemotherapy after the first-line treatment with a combi-

nation of fluorouracil and platinum agent in that 12 patients

(26 %) were pretreated only with postoperative adjuvant

chemotherapy while 5 patients (11 %) had already been

treated with two lines of treatment; (2) although post-

treatment cardiac function tests revealed that only one

patient showed[10 % reduction in the left ventricular

ejection fraction, other safety data are currently under

analysis and have not been published.

There is currently no evidence in support of efficacy or

safety for continuing with trastuzumab in case the patient

was pretreated with a trastuzumab-containing regimen

(trastuzumab beyond progression).


123

Compliance with ethical standards

Conflict of interest Dr. Kodera reports grants and personal fees from

Taiho Pharmaceutical, Chugai Phamaceutical, Sanofi, Merck Serono,

Yakult Honsha, Daiichi Sankyo, Otsuka Pharmaceutical Factory,

Takeda Pharmaceutical, Johnson & Johnson, Asahi Kasei Pharma, Eli

Lilly Japan, Pfizer Japan, AJINOMOTO Pharmaceuticals, ONO

Pharmaceutical and Kaken Pharmaceutical and grants from Covidien

Japan, Shionogi, Bristol Myers Squib, Japan Blood Products Orga-

nization, Torii Pharmaceutical, Mitsubishi Tanabe Pharma, bbVie

GK, Otsuka Pharmaceutical, Yoshindo, Eizai, Abbott Japan, CSL

Behring, Teijin Pharma, Tsumura, Nippon Kayaku, Miyarisan Phar-

maceutical, Novartis Pharmaceuticals Japan, KCI, Toyama Chemical,

Maruho, Hogy Medical and MSD, outside the submitted work.

Dr. Sano reports personal fees from Chugai Phamaceutical, Covidien

Japan, Eli Lilly Japan, Johnson & Johnson, Olympus, Otsuka Phar-

maceutical Factory, Taiho Pharmaceutical and Yakult Honsha.

Open Access This article is distributed under the terms of the Creative

Commons Attribution 4.0 International License (http://creative

commons.org/licenses/by/4.0/), which permits unrestricted use, distri-

bution, and reproduction in any medium, provided you give appropriate

credit to the original author(s) and the source, provide a link to the

Creative Commons license, and indicate if changes were made.

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